Project Summary/Abstract (Description) Significance: Non-tuberculous mycobacteria (NTM) respiratory infections is increasing across the globe. In the US, in those over 65 years-old, annual prevalence of pulmonary NTM disease increased significantly from 20 to 47 cases/100,000 between 1997-2007 with Hawaii having the highest prevalence at 396 cases/100,000. Pulmonary NTM is 1.4 times more common in women. These numbers are likely underestimated because of a lack of mandatory reporting in the U.S. Treatment of non-tuberculous mycobacterial lung disease is challenging for several reasons including the relative resistance to currently available drugs and the difficulty in tolerating prolonged treatment with multiple drugs. The only oral drugs with reliable activity against M. abscessus complex an NTM are the macrolides and clofazimine. Similar to that for M. avium complex, clofazimine was found to synergize with clarithromycin or amikacin against M. abscessus Clofazimine is an attractive agent for treatment of NTM respiratory infections including M. abscessus but cutaneous and internal organ accumulation from high oral doses cause significant toxicity. High oral doses are required to reach effective concentrations in the lungs. Inhaled doses of clofazimine have the potential to reach immediate treatment concentrations in the lungs with inhaled low doses that do not have significant systemic toxicity. Preliminary Data: Aerophase has recently demonstrated that innovative aerosol formulations of clofazimine with a new type of aerosol drug inhaler can treat TB respiratory infections without side effects from systemic toxicity. The new clofazimine formulation and aerosol device has demonstrated sustained pulmonary treatment concentration and an aerosol size range that can target the entire lung with clofazimine even alveolar regions. The Aerophase inhaled aerosol delivery method holds great promise to mitigate toxicity and allow for safe clofazimine administration directly targeted to the site of infection. Specific Aims: The first aim of this project is to treat NTM respiratory infections with inhaled clofazimine much more effectively than oral clofazimine with much lower inhaled dose. The second aim is to develop a small pocket sized metered dose inhaler with drug formulation, aerosol size, and dose optimized to treat NTM respiratory infections. The third aim will test in-vivo efficacy of inhaled clofazimine in combination with other drugs.